1. Field of the invention
The invention relates to a method for crystallizing a-L-aspartyl-L-phenylalanine methyl ester (aspartame), and more particularly, to a method for crystallizing aspartame by passing dispersed droplets comprising water and aspartame through water-immiscible fluids to generate a state of initial relative supersaturation within the dispersed droplets.
2. Description of the Related Art
Aspartame is the a-dipeptide ester L-aspartyl-L-phenylalanine methyl ester ("APM"). As an important synthetic low-calorie sweetening agent, aspartame is about 200 times as sweet as sugar with an exceptionally good taste pattern, but without a bitter aftertaste. This sweetener is used in a wide range of products such as soft drinks, sweets, table-top sweeteners, pharmaceutical products, and the like.
Aspartame can be prepared by several routes. One route, for example, involves the chemical coupling of N-protected L-aspartic acid or the anhydride thereof and (L-)phenylalanine or the methyl ester thereof. The protecting group is optionally removed later, and aspartame can be obtained by esterification if still necessary. Examples of such a process are disclosed in, for example, U.S. Pat. No. 3,786,039, the complete disclosure of which is hereby incorporated by reference. In processes for the preparation of aspartame by chemical coupling, relatively large amounts of .beta.-APM are usually formed as a side-product. Work-up of the desired .alpha.-APM often occurs through formation of, for example, the APM.HCl-salt followed by neutralization crystallization. Such methods inevitably lead to the production of large amounts of inorganic salt.
There also exist enzymatic processes for the production of aspartame, whereby, for instance, N-protected L-aspartic acid and (DL-)-phenylalanine methyl ester are selectively coupled to form the LL-.alpha.-dipeptide derivative, which is subsequently converted to aspartame. Such a process is described in, for example, U.S. Pat. No. 4,116,768, the complete disclosure of which is hereby incorporated by reference.
In any aspartame production process, one of the final process steps is to obtain aspartame in crystalline form from the solvent in which it is present. However, reaction by-products and/or decomposition products are also present. Usually, the solvent is an aqueous solvent. An aqueous solvent can be either water or a mixed solvent of water and up to about 25% (wt.) of a water-miscible organic solvent such as, for example, a lower alcohol having one to three carbon atoms. As used hereinafter, the term aqueous encompasses either water or water containing up to about 25% (wt.) of a C.sub.1-3 alcohol.
The term aspartame does not encompass physiologically acceptable salts of aspartame such as the hydrochloric acid salt (APM.HCl), but may include aspartame obtained from neutralization of such salts.
A method for crystallizing aspartame from aqueous solutions is described in U.S. Pat. Nos. 5,041,607 and 5,097,060, the complete disclosures of which are hereby incorporated by reference. According to this method, aspartame is substantially crystallized using conductive heat transfer for cooling without effecting forced flow, i.e. under conditions in which turbulence is avoided. This so-called static crystallization method requires special crystallization equipment and results in the formation of a hard, sherbet-like, pseudo-solid phase. Because of the limited method of cooling, it is not possible to obtain a heat transfer coefficient above approximately 100 W/m.sup.2.K on average during cooling, which means that the cooling time is relatively long. For example, it is believed that complete cooling and crystallization may take more than 3 hours in this process. Moreover, it has been found that aspartame crystals obtained by this static crystallization method are difficult to handle in a wet granulating process. The method yields unsuitable granulated products. These disadvantages of the prior art process are substantial.
In addition, a method for quickly cooling and crystallizing aspartame from aqueous solutions has been described in EP-A-0523813, the complete disclosure of which is hereby incorporated by reference. Cooling is achieved by direct contact of the aspartame solution with ice. However, the method is disadvantageous because cooling is not equally efficient throughout the whole aspartame solution and extensive dilution of the aspartame solution occurs due to the melting of large amounts of ice.